RESUMO
Monkeypox (MPXV) is one of the infectious viruses which caused morbidity and mortality problems in these years. Despite its danger to public health, there is no approved drug to stand and handle MPXV. On the other hand, drug repurposing is a promising screening method for the low-cost introduction of approved drugs for emerging diseases and viruses which utilizes computational methods. Therefore, drug repurposing is a promising approach to suggesting approved drugs for the MPXV. This paper proposes a computational framework for MPXV antiviral prediction. To do this, we have generated a new virus-antiviral dataset. Moreover, we applied several machine learning and one deep learning method for virus-antiviral prediction. The suggested drugs by the learning methods have been investigated using docking studies. The target protein structure is modeled using homology modeling and, then, refined and validated. To the best of our knowledge, this work is the first work to study deep learning methods for the prediction of MPXV antivirals. The screening results confirm that Tilorone, Valacyclovir, Ribavirin, Favipiravir, and Baloxavir marboxil are effective drugs for MPXV treatment.
Assuntos
Antivirais , Aprendizado Profundo , Reposicionamento de Medicamentos , Monkeypox virus , Antivirais/farmacologia , Monkeypox virus/efeitos dos fármacos , Reposicionamento de Medicamentos/métodos , Pirazinas/farmacologia , Simulação de Acoplamento Molecular , Dibenzotiepinas , Amidas/farmacologia , Ribavirina/farmacologia , Triazinas/farmacologia , Mpox/tratamento farmacológico , Mpox/virologia , Humanos , Aprendizado de Máquina , Morfolinas , PiridonasRESUMO
Advancements in human-engineered heart tissue have enhanced the understanding of cardiac cellular alteration. Nevertheless, a human model simulating pathological remodeling following myocardial infarction for therapeutic development remains essential. Here we develop an engineered model of myocardial repair that replicates the phased remodeling process, including hypoxic stress, fibrosis, and electrophysiological dysfunction. Transcriptomic analysis identifies nine critical signaling pathways related to cellular fate transitions, leading to the evaluation of seventeen modulators for their therapeutic potential in a mini-repair model. A scoring system quantitatively evaluates the restoration of abnormal electrophysiology, demonstrating that the phased combination of TGFß inhibitor SB431542, Rho kinase inhibitor Y27632, and WNT activator CHIR99021 yields enhanced functional restoration compared to single factor treatments in both engineered and mouse myocardial infarction model. This engineered heart tissue repair model effectively captures the phased remodeling following myocardial infarction, providing a crucial platform for discovering therapeutic targets for ischemic heart disease.
Assuntos
Dioxóis , Fibrose , Infarto do Miocárdio , Piridinas , Engenharia Tecidual , Animais , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/genética , Camundongos , Humanos , Piridinas/farmacologia , Piridinas/uso terapêutico , Engenharia Tecidual/métodos , Dioxóis/farmacologia , Dioxóis/uso terapêutico , Miocárdio/patologia , Miocárdio/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Modelos Animais de Doenças , Transdução de Sinais , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Remodelação Ventricular/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Coração/fisiopatologia , Coração/efeitos dos fármacos , AmidasRESUMO
In this work, we describe an improved series of N-phenylpyrrolamide inhibitors that exhibit potent activity against DNA gyrase and are highly effective against high-priority gram-positive bacteria. The most potent compounds show low nanomolar IC50 values against Escherichia coli DNA gyrase, and in addition, compound 7c also inhibits E. coli topoisomerase IV in the nanomolar concentration range, making it a promising candidate for the development of potent dual inhibitors for these enzymes. All tested compounds show high selectivity towards the human isoform DNA topoisomerase IIα. Compounds 6a, 6d, 6e and 6f show MIC values between 0.031 and 0.0625 µg/mL against vancomycin-intermediate S. aureus (VISA) and Enterococcus faecalis strains. Compound 6g shows an inhibitory effect against the methicillin-resistant S. aureus strain (MRSA) with a MIC of 0.0625 µg/mL and against the E. faecalis strain with a MIC of 0.125 µg/mL. In a time-kill assay, compound 6d showed a dose-dependent bactericidal effect on the MRSA strain and achieved bactericidal activity at 8 × MIC after 8 h. The duration of the post-antibiotic effect (PAE) on the MRSA strain for compound 6d was 2 h, which corresponds to the PAE duration for ciprofloxacin. The compounds were not cytotoxic at effective concentrations, as determined in an MTS assay on the MCF-7 breast cancer cell line.
Assuntos
Antibacterianos , DNA Girase , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Inibidores da Topoisomerase II , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Humanos , Inibidores da Topoisomerase II/farmacologia , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/síntese química , DNA Girase/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular , Enterococcus faecalis/efeitos dos fármacos , Pirróis/farmacologia , Pirróis/química , Pirróis/síntese química , Amidas/farmacologia , Amidas/química , Amidas/síntese química , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacosRESUMO
In search for new molecules of diterpene origin with promising anticancer activity, two amino-derivatives (methyl maleopimarate aminoimide and methyl 1ß,13-epoxydihydroquinopimarate C4-hydrazone) were involved in the 4-component Ugi reaction (Ugi-4CR) and pseudo-7-component azido-Ugi condensation (azido-Ugi-7CR) to afford a series of adducts holding α-aminoacylamide and bis-1,5-disubstituted tetrazole substituents. The NCI-60 cancer cell panel screening revealed diterpene-type Ugi adducts 2, 5, and 6 with strong antiproliferative potency with GI50 in range of 1.2-15.4 µM. The high positive correlations with standard anticancer drugs suggest microtubules or progesterone and androgen receptors as possible targets of the synthesized compounds.
Assuntos
Antineoplásicos , Diterpenos , Tetrazóis , Humanos , Tetrazóis/química , Tetrazóis/síntese química , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Diterpenos/química , Diterpenos/farmacologia , Diterpenos/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Amidas/químicaRESUMO
BACKGROUND: Glaucoma is a leading cause of blindness, affecting retinal ganglion cells (RGCs) and their axons. By 2040, it is likely to affect 110 million people. Neuroinflammation, specifically through the release of proinflammatory cytokines by M1 microglial cells, plays a crucial role in glaucoma progression. Indeed, in post-mortem human studies, pre-clinical models, and ex-vivo models, RGC degeneration has been consistently shown to be linked to inflammation in response to cell death and tissue damage. Recently, Rho kinase inhibitors (ROCKis) have emerged as potential therapies for neuroinflammatory and neurodegenerative diseases. This study aimed to investigate the potential effects of three ROCKis (Y-27632, Y-33075, and H-1152) on retinal ganglion cell (RGC) loss and retinal neuroinflammation using an ex-vivo retinal explant model. METHODS: Rat retinal explants underwent optic nerve axotomy and were treated with Y-27632, Y-33075, or H-1152. The neuroprotective effects on RGCs were evaluated using immunofluorescence and Brn3a-specific markers. Reactive glia and microglial activation were studied by GFAP, CD68, and Iba1 staining. Flow cytometry was used to quantify day ex-vivo 4 (DEV 4) microglial proliferation and M1 activation by measuring the number of CD11b+, CD68+, and CD11b+/CD68+ cells after treatment with control solvent or Y-33075. The modulation of gene expression was measured by RNA-seq analysis on control and Y-33075-treated explants and glial and pro-inflammatory cytokine gene expression was validated by RT-qPCR. RESULTS: Y-27632 and H-1152 did not significantly protect RGCs. By contrast, at DEV 4, 50 µM Y-33075 significantly increased RGC survival. Immunohistology showed a reduced number of Iba1+/CD68+ cells and limited astrogliosis with Y-33075 treatment. Flow cytometry confirmed lower CD11b+, CD68+, and CD11b+/CD68+ cell numbers in the Y-33075 group. RNA-seq showed Y-33075 inhibited the expression of M1 microglial markers (Tnfα, Il-1ß, Nos2) and glial markers (Gfap, Itgam, Cd68) and to reduce apoptosis, ferroptosis, inflammasome formation, complement activation, TLR pathway activation, and P2rx7 and Gpr84 gene expression. Conversely, Y-33075 upregulated RGC-specific markers, neurofilament formation, and neurotransmitter regulator expression, consistent with its neuroprotective effects. CONCLUSION: Y-33075 demonstrates marked neuroprotective and anti-inflammatory effects, surpassing the other tested ROCKis (Y-27632 and H-1152) in preventing RGC death and reducing microglial inflammatory responses. These findings highlight its potential as a therapeutic option for glaucoma.
Assuntos
Fármacos Neuroprotetores , Piridinas , Células Ganglionares da Retina , Quinases Associadas a rho , Animais , Piridinas/farmacologia , Quinases Associadas a rho/metabolismo , Quinases Associadas a rho/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Ratos , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Retina/efeitos dos fármacos , Retina/patologia , Retina/metabolismo , Amidas/farmacologia , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Ratos Sprague-Dawley , Neuroproteção/efeitos dos fármacos , Neuroproteção/fisiologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Inibidores de Proteínas Quinases/farmacologia , Masculino , Traumatismos do Nervo Óptico/tratamento farmacológico , Traumatismos do Nervo Óptico/patologia , Traumatismos do Nervo Óptico/metabolismo , Isoquinolinas , SulfonamidasRESUMO
This narrative review provides an overview of current knowledge on the impact of nutritional strategies on chronic craniofacial pain associated with temporomandibular disorders (TMDs). Individuals experiencing painful TMDs alter their dietary habits, avoiding certain foods, possibly due to chewing difficulties, which might lead to nutrient deficiencies. Our literature investigation revealed that the causal links between nutritional changes and craniofacial pain remain unclear. However, clinical and preclinical studies suggest that nutraceuticals, including vitamins, minerals, polyphenols, omega-3 fatty acids, isoprenoids, carotenoids, lectins, polysaccharides, glucosamines, and palmitoylethanolamides, could have beneficial effects on managing TMDs. This is described in 12 clinical and 38 preclinical articles since 2000. Clinical articles discussed the roles of vitamins, minerals, glucosamine, and palmitoylethanolamides. The other nutraceuticals were assessed solely in preclinical studies, using TMD models, mostly craniofacial inflammatory rodents, with 36 of the 38 articles published since 2013. Our investigation indicates that current evidence is insufficient to assess the efficacy of these nutraceuticals. However, the existing data suggest potential for therapeutic intervention in TMDs. Further support from longitudinal and randomized controlled studies and well-designed preclinical investigations is necessary to evaluate the efficacy of each nutraceutical intervention and understand their underlying mechanisms in TMDs.
Assuntos
Dor Crônica , Suplementos Nutricionais , Dor Facial , Transtornos da Articulação Temporomandibular , Transtornos da Articulação Temporomandibular/dietoterapia , Humanos , Dor Facial/dietoterapia , Dor Facial/etiologia , Dor Crônica/dietoterapia , Dor Crônica/terapia , Animais , Ácidos Graxos Ômega-3/administração & dosagem , Glucosamina/administração & dosagem , Vitaminas/administração & dosagem , Amidas , Etanolaminas , Ácidos PalmíticosRESUMO
Rationale: Tunnel nanotube (TNT)-mediated mitochondrial transport is crucial for the development and maintenance of multicellular organisms. Despite numerous studies highlighting the significance of this process in both physiological and pathological contexts, knowledge of the underlying mechanisms is still limited. This research focused on the role of the ROCK inhibitor Y-27632 in modulating TNT formation and mitochondrial transport in retinal pigment epithelial (RPE) cells. Methods: Two types of ARPE19 cells (a retinal pigment epithelial cell line) with distinct mitochondrial fluorescently labeled, were co-cultured and treated with ROCK inhibitor Y-27632. The formation of nanotubes and transport of mitochondria were assessed through cytoskeletal staining and live cell imaging. Mitochondrial dysfunction was induced by light damage to establish a model, while mitochondrial function was evaluated through measurement of oxygen consumption rate. The effects of Y-27632 on cytoskeletal and mitochondrial dynamics were further elucidated through detailed analysis. Results: Y-27632 treatment led to an increase in nanotube formation and enhanced mitochondrial transfer among ARPE19 cells, even following exposure to light-induced damage. Our analysis of cytoskeletal and mitochondrial distribution changes suggests that Y-27632 promotes nanotube-mediated mitochondrial transport by influencing cytoskeletal remodeling and mitochondrial movement. Conclusions: These results suggest that Y-27632 has the ability to enhance mitochondrial transfer via tunneling nanotubes in retinal pigment epithelium, and similarly predict that ROCK inhibitor can fulfill its therapeutic potential through promoting mitochondrial transport in the retinal pigment epithelium in the future.
Assuntos
Amidas , Mitocôndrias , Nanotubos , Piridinas , Epitélio Pigmentado da Retina , Quinases Associadas a rho , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/efeitos dos fármacos , Humanos , Amidas/farmacologia , Piridinas/farmacologia , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Quinases Associadas a rho/metabolismo , Quinases Associadas a rho/antagonistas & inibidores , Linhagem Celular , Citoesqueleto/metabolismo , Citoesqueleto/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacosRESUMO
A library of C-3 functionalized flavones was successfully provided via palladium-catalyzed amino- and aryloxycarbonylation reactions of 3-iodoflavone (1), under mild conditions. This methodology showed good functional group tolerance using a variety of amines and phenols, under an atmospheric pressure of carbon monoxide as a carbonyl source. While the flavone-3-carboxamides (2a-t) were produced in 22-79%, the flavone-3-carboxylates (4a'-l') were obtained in excellent yields (up to 88%), under identical reaction conditions, just by switching N-nucleophiles to O-nucleophiles. The convenient availability of the involved starting materials confers simplicity to this approach to design new C-3-substituted flavones of biological relevance. The solid-state structures of flavone-3-carboxamide (2r) and flavone-3-ester (4f') were further studied by single-crystal XRD analysis.
Assuntos
Flavonas , Paládio , Paládio/química , Catálise , Flavonas/química , Ácidos Carboxílicos/química , Estrutura Molecular , Amidas/química , Aminas/químicaRESUMO
AIM: To investigate the efficacy of Palmitoylethanolamide (PEA, 300 mg), Superoxide Dismutase (SOD, 70 UI), Alpha Lipoic Acid (ALA, 300 mg), vitamins B6 (1.5 mg), B1 (1.1 mg), B12 (2.5 mcg), E (7.5 mg), nicotinamide (9 mg), and minerals (Mg 30 mg, Zn 2.5 mg) in one tablet in people with Diabetic Neuropathy (DN). PATIENTS-METHODS: In the present pilot study, 73 people (age 63.0 ± 9.9 years, 37 women) with type 2 Diabetes Mellitus (DMT2) (duration 17.5 ± 7.3 years) and DN were randomly assigned to receive either the combination of ten elements (2 tablets/24 h) in the active group (n = 36) or the placebo (n = 37) for 6 months. We used the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE), measured vibration perception threshold (VPT) with biothesiometer, and Cardiovascular Autonomic Reflex Tests (CARTs). Nerve function was assessed by DPN Check [sural nerve conduction velocity (SNCV) and amplitude (SNAP)]. Sudomotor function was assessed with SUDOSCAN, which measures electrochemical skin conductance in hands and feet (ESCH and ESCF). Pain score (PS) was assessed with Pain DETECT questionnaire. Quality of life was assessed by questionnaire. RESULTS: In the active group, there was a large improvement of pain (PS from 20.9 to 13.9, p < 0.001). There was also a significant improvement of vitamin B12 (B12) levels, MNSIQ, SNCV, VPT, and ESCF (222.1 vs. 576.3 pg/ mL, p < 0.001; 6.1 vs. 5.9, p = 0.017; 28.8 vs. 30.4, p = 0.001; 32.1 vs. 26.7, p = 0.001; and 72.2 vs. 74.8, p < 0.001 respectively). In the placebo group, neither pain (21.6 vs. 21.7, p = 0.870) or any other aforementioned parameters changed significantly, and MNSIE worsened (2.9 vs. 3.4, p < 0.001). As a result, changes from baseline to follow-up in pain, B12 levels, VPT, and MNSIQ differed significantly between the two groups (p < 0.001, 0.025, 0.009, and <0.001, respectively). CARTs, SNAP, ESCH did not significantly change in either of the two groups. CONCLUSIONS: The combination of the ten elements in one tablet for 6 months at a daily dose of two tablets in people with DN significantly improves pain, vibration perception threshold, and B12 levels.
Assuntos
Amidas , Neuropatias Diabéticas , Etanolaminas , Niacinamida , Ácidos Palmíticos , Superóxido Dismutase , Ácido Tióctico , Vitamina B 12 , Vitamina B 6 , Humanos , Pessoa de Meia-Idade , Feminino , Neuropatias Diabéticas/tratamento farmacológico , Masculino , Idoso , Vitamina B 12/administração & dosagem , Ácido Tióctico/administração & dosagem , Projetos Piloto , Vitamina B 6/administração & dosagem , Ácidos Palmíticos/administração & dosagem , Etanolaminas/administração & dosagem , Niacinamida/administração & dosagem , Niacinamida/uso terapêutico , Amidas/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Zinco/administração & dosagem , Vitamina E/administração & dosagem , Método Duplo-Cego , Tiamina/administração & dosagem , Resultado do Tratamento , Suplementos NutricionaisRESUMO
The biosynthesis of fatty acids constitutes a critical metabolic pathway in bacterial organisms. Prior investigations have highlighted the synthesis of antimicrobial compounds anchored in the benzodioxepin scaffold, noted for their pronounced antibacterial properties. Leveraging this foundational knowledge, the current research endeavors to meticulously engineer and synthesize a series of eight innovative benzodioxepin amide-biphenyl derivatives. This achievement was realized through the sophisticated optimization of synthetic methodologies. The scope of this study extends to a rigorous evaluation of the antibacterial prowess and biocompatibility of the aforementioned novel derivatives. Notably, Compound E4 emerged as a supremely potent antimicrobial agent. A detailed elucidation of the crystalline architecture of Compound E4 was conducted, alongside a thorough docking study to explore its interactions with the FabH enzyme.
Assuntos
Amidas , Antibacterianos , Compostos de Bifenilo , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Amidas/farmacologia , Amidas/química , Amidas/síntese química , Compostos de Bifenilo/química , Simulação de Acoplamento Molecular , Benzodioxóis/farmacologia , Benzodioxóis/síntese química , Benzodioxóis/química , Relação Estrutura-Atividade , Staphylococcus aureus/efeitos dos fármacos , Estrutura MolecularRESUMO
RATIONALE: Anesthetics are widely used for optimizing surgical conditions, postoperative pain management, and treating various chronic pain conditions. Tetracaine and decamethonium are representative drugs of local anesthetics and neuromuscular blocking agents, respectively. However, overdose and toxicity of the drugs always lead to serious adverse events. Thus, there is a strong demand for effective antidotes. METHODS: The binding interactions of amide naphthotubes with tetracaine and decamethonium were systematically studied using 1H NMR, ITC, and DFT calculations. The antidotal effects of amide naphthotube to tetracaine toxicity were assessed in vitro and in vivo, and the mechanism of detoxification was explored at a cellular level. Additionally, mouse models were established to evaluate the reversal activities of amide naphthotube on decamethonium-induced mortality and muscle relaxation, and the reversal mechanism was investigated through pharmacokinetic experiments. RESULTS: We have demonstrated that the anti-isomer of amide naphthotube exhibits significant binding affinities towards tetracaine (K a = 1.89×107 M-1) and decamethonium (K a = 1.01×107 M-1) in water. The host displayed good biocompatibility both in vitro and in vivo. The administration of amide naphthotube following tetracaine overdose in mouse models notably increased the overall survival rate, indicating its effective antidotal properties. The host could reverse the tetracaine-induced Na+ channels blockage at the cellular level. Moreover, the injection of amide naphthotube also reversed the mortality and paralysis induced by decamethonium in mouse models following a pharmacokinetic mechanism. CONCLUSION: An emerging artificial receptor, amide naphthotube, has strong binding affinities towards tetracaine and decamethonium. It functions as a supramolecular antidote for tetracaine poisoning and a reversal agent for decamethonium by selectively sequestering these compounds in vivo.
Assuntos
Antídotos , Tetracaína , Animais , Tetracaína/farmacologia , Tetracaína/química , Camundongos , Antídotos/farmacologia , Antídotos/química , Amidas/química , Amidas/farmacologia , Masculino , Anestésicos Locais/farmacologia , Anestésicos Locais/química , Humanos , Bloqueadores Neuromusculares/química , Bloqueadores Neuromusculares/farmacologiaAssuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Emtricitabina , Infecções por HIV , HIV-1 , Compostos Heterocíclicos com 3 Anéis , Oxazinas , Piperazinas , Piridonas , Tenofovir , Humanos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/genética , Emtricitabina/uso terapêutico , Piridonas/uso terapêutico , Piperazinas/uso terapêutico , Tenofovir/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Oxazinas/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Hepatite B/tratamento farmacológico , Adenina/análogos & derivados , Adenina/uso terapêutico , Masculino , Feminino , AmidasRESUMO
BACKGROUND: Head-to-head data for bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF; B) and darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/c/F/TAF; D) are lacking in the context of rapid antiretroviral therapy (ART) initiation. This study, BIC-T&T, evaluates the efficacy and tolerability of B vs D in a UK test-and-treat setting. SETTING: BIC-T&T was a randomised, open-label, multi-centre, study in which participants initiated ART within 14 days after confirmed HIV-1 diagnosis before baseline laboratory. METHODS: The primary endpoint is the virological response (HIV RNA < 50copies/mL) at week 12 by time-weighted average change in log10 HIV RNA recorded in viral load assays from treatment initiation to week 12, using two-sample Wilcoxon rank-sum test. RESULTS: 36 participants were randomised: 94% were male, 53% white; mean (SD) age was 35 years (11.8). Baseline mean (±SD) log10 HIV-RNA was 4.79 (± 0.87) log10 copies/mL and CD4 505 (±253) cells/mm3. The mean (±SD) time from confirmed HIV diagnosis to ART initiation was 7.9 (± 3.7) days. The time-weighted mean decrease in log10 HIV RNA from treatment initiation to week 12 was significantly greater in B in comparison to D (3.1 vs. 2.6 log10 copies/mL, p < 0.001). Both regimens demonstrated good tolerability with infrequent laboratory abnormalities and no grade 3 or 4 adverse events. CONCLUSION: In this first head-to-head study in the context of ART initiation, HIV RNA decline from baseline to week 12 was significantly more rapid for BIC/F/TAF compared with DRV/c/F/TAF.
Assuntos
Fármacos Anti-HIV , Emtricitabina , Infecções por HIV , Tenofovir , Carga Viral , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Masculino , Feminino , Adulto , Tenofovir/uso terapêutico , Tenofovir/análogos & derivados , Fármacos Anti-HIV/uso terapêutico , Carga Viral/efeitos dos fármacos , Emtricitabina/uso terapêutico , HIV-1/efeitos dos fármacos , HIV-1/genética , Adenina/análogos & derivados , Adenina/uso terapêutico , Piperazinas/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Darunavir/uso terapêutico , Alanina/uso terapêutico , Alanina/análogos & derivados , Resultado do Tratamento , RNA Viral , Sulfonamidas/uso terapêutico , Pessoa de Meia-Idade , Cobicistat/uso terapêutico , Reino Unido , Combinação de Medicamentos , Amidas , PiridonasRESUMO
As an important small organic molecule, cyclopropane is widely used in drug design. In this paper, fifty-three amide derivatives containing cyclopropane were designed and synthesized by introducing amide groups and aryl groups into cyclopropane through the active splicing method, and their antibacterial and antifungal activities were evaluated in vitro. Among them, thirty-five compounds were new compounds, and eighteen compounds were known compounds (F14, F15, F18, F20-F26, F36, and F38-F44). Bioassay results disclosed that four, three, and nine of the compounds showed moderate activity against Staphylococcus aureus, Escherichia coli, and Candida albicans, respectively. Three compounds were sensitive to Candida albicans, with excellent antifungal activity (MIC80 = 16 µg/mL). The molecular docking results show that compounds F8, F24, and F42 have good affinity with the potential antifungal drug target CYP51 protein.
Assuntos
Amidas , Antifúngicos , Candida albicans , Ciclopropanos , Desenho de Fármacos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Staphylococcus aureus , Ciclopropanos/farmacologia , Ciclopropanos/química , Ciclopropanos/síntese química , Amidas/química , Amidas/farmacologia , Amidas/síntese química , Candida albicans/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Escherichia coli/efeitos dos fármacos , Relação Estrutura-Atividade , Anti-Infecciosos/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Antibacterianos/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Estrutura MolecularRESUMO
BACKGROUND: It was reported that either shorter programmed intermittent epidural bolus (PIEB) intervals or high-speed bolus can produce more extensive epidural spread. We hypothesized that a combination of shortened time interval and increased speed of epidural bolus might further improve analgesic effect and therefore reduce the hourly volume for epidural labour analgesia. METHODS: This double-blind dose-finding study used a biased coin up-and-down sequential allocation method to determine the 90% effective bolus volume of ropivacaine combined with sufentanil while using the push pump at a rate of 400 mL/hr and interval of 30 min to provide effective analgesia without breakthrough pain. We used 0.1% ropivacaine with 0.4 µg/mL sufentanil, with bolus volumes ranging from 3 to 6 mL. The first patient was assigned a volume of 3 mL, and the remaining volumes were assigned according to the biased coin-up-and-down method. RESULTS: The estimated 90% effective volume (EV90) of ropivacaine combined with sufentanil for epidural labour analgesia at a time interval of 30 min was 4.88 mL (95% confidence interval 4.83-5.38). CONCLUSIONS: The optimum bolus volume of ropivacaine with sufentanil while using push pump at a time interval of 30 min is approximately 5 mL. It could probably further reduce the hourly bolus volume for epidural labour analgesia.
Assuntos
Amidas , Analgesia Epidural , Analgesia Obstétrica , Anestésicos Locais , Ropivacaina , Sufentanil , Humanos , Ropivacaina/administração & dosagem , Sufentanil/administração & dosagem , Método Duplo-Cego , Feminino , Analgesia Epidural/métodos , Gravidez , Adulto , Anestésicos Locais/administração & dosagem , Analgesia Obstétrica/métodos , Amidas/administração & dosagem , Analgésicos Opioides/administração & dosagem , Relação Dose-Resposta a Droga , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Preoperative prediction of lymphovascular space invasion (LVSI) is crucial for improving the prognosis of patients with cervical cancer. PURPOSE: To evaluate the value of preoperative amide proton transfer (APT) imaging combined with serum CA125 levels for predicting LVSI in cervical cancer. MATERIAL AND METHODS: This retrospective study included 80 patients with cervical cancer who underwent preoperative magnetic resonance imaging, including APT imaging. Serum CA125 levels were measured using a fully automated immunoassay analyzer and chemiluminescence method. The presence of LVSI was determined based on the pathological results after surgery. RESULTS: Among the 40 patients who met the requirements, 29 had postoperative pathological confirmation of LVSI, while 11 did not. The areas under the receiver operating characteristic curves (AUC) of preoperative APT and CA125 levels predicting LVSI were 0.889 and 0.687, respectively. When the APT value was 2.9%, the corresponding Youden index was the highest (0.702), with a sensitivity of 79.3% and specificity of 90.9%. When the critical value of the preoperative serum CA15 level was 25.3â u/mL, the corresponding Youden index was the highest (0.508), with a sensitivity of 69.0% and a specificity of 81.8%. The sensitivity and specificity of preoperative APT imaging combined with serum CA125 in predicting LVSI were 82.7% and 100%, respectively, with a Youden's index of 0.828 and an AUC of 0.923. CONCLUSION: The combination of preoperative APT imaging and serum CA125 levels is valuable for predicting LVSI in cervical cancer. Diagnostic efficacy is highest when the APT value is >2.9% and the serum CA125 level is >25.3â u/mL.
Assuntos
Antígeno Ca-125 , Imageamento por Ressonância Magnética , Invasividade Neoplásica , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/cirurgia , Neoplasias do Colo do Útero/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Antígeno Ca-125/sangue , Adulto , Imageamento por Ressonância Magnética/métodos , Idoso , Sensibilidade e Especificidade , Metástase Linfática/diagnóstico por imagem , Valor Preditivo dos Testes , Amidas , Prótons , Cuidados Pré-Operatórios/métodos , Biomarcadores Tumorais/sangueRESUMO
In this work, we performed anti-proliferative assays for the compound N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) on breast cancer (BC) cells (MCF-7, SKBR3, and triple-negative BC (TNBC) MDA-MB-231 cells) to explore its pharmacological mechanism regarding the type of cell death associated with G protein-coupled estrogen receptor (GPER) expression. The results show that HO-AAVPA induces cell apoptosis at 5 h or 48 h in either estrogen-dependent (MCF-7) or -independent BC cells (SKBR3 and MDA-MB-231). At 5 h, the apoptosis rate for MCF-7 cells was 68.4% and that for MDA-MB-231 cells was 56.1%; at 48 h, that for SKBR3 was 61.6%, that for MCF-7 cells was 54.9%, and that for MDA-MB-231 (TNBC) was 43.1%. HO-AAVPA increased the S phase in MCF-7 cells and reduced the G2/M phase in MCF-7 and MDA-MB-231 cells. GPER expression decreased more than VPA in the presence of HO-AAVPA. In conclusion, the effects of HO-AAVPA on cell apoptosis could be modulated by epigenetic effects through a decrease in GPER expression.
Assuntos
Apoptose , Neoplasias da Mama , Pontos de Checagem do Ciclo Celular , Receptores de Estrogênio , Receptores Acoplados a Proteínas G , Humanos , Apoptose/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores de Estrogênio/metabolismo , Feminino , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Células MCF-7 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Amidas/farmacologia , Amidas/químicaRESUMO
Supervised field trial studies were conducted to understand dissipation kinetics and harvest time residues of a combination product of fluxapyroxad and pyraclostrobin in cumin plant/leaves and seeds at different locations in India. The results showed initial accumulation of fluxapyroxad at the levels of 15.4 and 20.2 mg kg-1 and pyraclostrobin at the level of 21.2 and 33.4 mg kg-1 in cumin leaves/plant in Anand, Gujarat. Fluxapyroxad and pyraclostrobin followed zero-order and first-order dissipation kinetics in cumin plant/leaves samples respectively. The residues translocated to cumin seeds. As the hazard quotient (HQ) was <1 in all cases consumer health risk may be negligible.
Assuntos
Cuminum , Fungicidas Industriais , Estrobilurinas , Estrobilurinas/análise , Estrobilurinas/química , Fungicidas Industriais/análise , Fungicidas Industriais/química , Cinética , Cuminum/química , Medição de Risco , Resíduos de Praguicidas/análise , Índia , Pirazóis/análise , Pirazóis/química , Sementes/química , Folhas de Planta/química , Contaminação de Alimentos/análise , AmidasRESUMO
Dual-target agents have more advantages than drug combinations for cancer treatment. Here, we designed and synthesized a series of novel VEGFR-2/tubulin dual-target inhibitors through a molecular hybridization strategy, and the activities of all the synthesized compounds were tested against tubulin and VEGFR-2. Among which, compound 19 exhibited strong potency against tubulin and VEGFR-2, with IC50 values of 0.76 ± 0.11 µM and 15.33 ± 2.12 nM, respectively. Additionally, compound 19 not only had significant antiproliferative effects on a series of human cancer cell lines, especially MGC-803 cells (IC50 = 0.005 ± 0.001 µM) but also overcame drug resistance in Taxol-resistant MGC-803 cells, with an RI of 1.8. Further studies showed that compound 19 could induce tumor cell apoptosis by reducing the mitochondrial membrane potential, increasing the level of ROS, facilitating the induction of G2/M phase arrest, and inhibiting the migration and invasion of tumor cells in a dose-dependent manner. In addition, compound 19 also exhibits potent antiangiogenic effects by blocking the VEGFR-2/PI3K/AKT pathway and inhibiting the tubule formation, invasion, and migration of HUVECs. More importantly, compound 19 demonstrated favorable pharmacokinetic profiles, robust in vivo antitumor efficacy, and satisfactory safety profiles. Overall, compound 19 can be used as a lead compound for the development of tubulin/VEGFR-2 dual-target inhibitors.
Assuntos
Inibidores da Angiogênese , Antineoplásicos , Apoptose , Proliferação de Células , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Moduladores de Tubulina , Tubulina (Proteína) , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Humanos , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/química , Inibidores da Angiogênese/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Tubulina (Proteína)/metabolismo , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/síntese química , Apoptose/efeitos dos fármacos , Amidas/química , Amidas/farmacologia , Amidas/síntese química , Descoberta de Drogas , Animais , Linhagem Celular Tumoral , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Camundongos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacosRESUMO
BACKGROUND: There is a need to understand health care resource utilization (HCRU) and costs associated with treatment-experienced people with HIV (PWH) switching treatment regimens. OBJECTIVE: To describe HCRU and cost during lines of antiretroviral therapy (ART) for treatment-experienced PWH switching to or restarting guideline-recommended, integrase strand transfer inhibitor (INSTI)-based multitablet regimens and single-tablet regimens. METHODS: This retrospective claims study used data from Optum Research Database (January 1, 2010, to March 31, 2020) to identify lines of therapy (LOTs) for treatment-experienced adults who switched to or restarted INSTI-based regimens between January 1, 2018, and December 31, 2019. The first LOT during the study period was included in the analysis. We examined all-cause HCRU and costs and HIV-related HCRU and combined costs to the health plan and direct patient costs by site of service and compared between INSTI-based regimens: bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) (single tablet) vs dolutegravir/abacavir/lamivudine (DTG/ABC/3TC) (single tablet), dolutegravir + emtricitabine/tenofovir alafenamide (DTG+FTC/TAF) (multitablet), and dolutegravir + emtricitabine/tenofovir disoproxil fumarate (DTG+FTC/TDF) (multitablet). Analysis of HCRU by site of service was conducted following inverse probability treatment weighting. Multivariable regression was conducted using a generalized linear model with stepwise covariate selection to estimate HIV-related medical costs and control for remaining differences after inverse probability treatment weighting. RESULTS: 4,251 PWH were identified: B/F/TAF (n = 2,727; 64.2%), DTG/ABC/3TC (n = 898; 21.1%), DTG+FTC/TAF (n = 539; 12.7%), and DTG+FTC/TDF (n = 87; 2.1%). PWH treated with DTG+FTC/TAF had a significantly higher mean of all-cause ambulatory visits than PWH treated with B/F/TAF (1.8 vs 1.6, P < 0.001). A significantly smaller proportion of PWH treated with DTG/ABC/3TC had an all-cause ambulatory visit vs PWH treated with B/F/TAF (90.6% vs 93.9%, P < 0.001). All-cause total costs were not significantly different between regimens. Mean (SD) medical HIV-related costs per month during the LOT were not significantly different between B/F/TAF $699 (3,602), DTG/ABC/3TC $770 (3,469), DTG+FTC/TAF $817 (3,128), and DTG+FTC/TDF $3,570 (17,691). After further controlling for unbalanced measures, HIV-related medical costs during the LOT were higher (20%) but did not reach statistical significance for DTG/ABC/3TC (cost ratio = 1.20, 95% CI = 0.851-1.694; P = 0.299), 49% higher for DTG+FTC/TAF (cost ratio = 1.489, 95% CI = 1.018-2.179; P = 0.040), and almost 11 times greater for DTG+FTC/TDF (cost ratio = 10.759, 95% CI = 2.182-53.048; P = 0.004) compared with B/F/TAF. CONCLUSIONS: HIV-related medical costs during the LOT were lowest for PWH treated with INSTI-based single-tablet regimens. Simplifying treatment regimens may help PWH maintain lower health care costs.